E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045242 |
E.1.2 | Term | Type II diabetes mellitus |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To assess the effect of the addition of treatment with canagliflozin relative to the addition of placebo on hemoglobin A1c (HbA1c) after 26 weeks of treatment • To assess the safety and tolerability of canagliflozin
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E.2.2 | Secondary objectives of the trial |
After 26 weeks of treatment, to assess the effect of canagliflozin relative to placebo on: Bone mineral density at the lumbar spine, hip, and distal forearm as measured by dual energy X-ray absorptiometry (DXA); Markers of bone turnover; Proportion of subjects achieving HbA1c <7.0% and <6.5%; Fasting plasma glucose; Body weight; Fasting plasma lipids ; Systolic and diastolic blood pressure; Time to rescue therapy and proportion of subjects receiving rescue therapy; Body composition as measured by DXA in a subset of subjects. After 52 weeks of treatment, to assess the effect of canagliflozin relative to placebo on: Bone mineral density at the lumbar spine, hip, and distal forearm as measured by DXA; Glycemic control; Proportion of subjects achieving HbA1c <7.0% and <6.5%; Body weight; Fasting plasma lipids; Systolic and diastolic blood pressure. After 104 weeks of treatment, please refer to section 2.1.2 of the protocol for complete description.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The substudy in part of the main study. Related to bone strength: The main outcome parameters for this substudy will be vertebral strength for the spine, and femoral strength. Other important strength parameters, stiffness and strength to density ratios will also be assessed. Refer to section 9.9 of the protocol. |
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E.3 | Principal inclusion criteria |
• Man or woman > or=55 to < or =80 years of age at screening with T2DM; women must be at least 3 years postmenopausal • Has an HbA1c > or=7.0% to < or =10.0% at screening (or at Week -2, if HbA1c obtained more than 3 weeks prior to Week -2 visit), and – Not currently on AHA therapy (off for at least 12 weeks) or – On a stable regimen of AHA(s) in monotherapy or on combination therapy, with any approved class of agents (including metformin, SU, PPARgamma agent [ie, TZD], DPP-4 inhibitor, AGI, GLP-1 analogue, or insulin) used in accordance with local prescribing information, for at least 12 weeks prior to screening visit (and at least 6 months for subjects on a PPARgamma agent) Note: a stable dose of insulin is defined as no change in the insulin regimen (ie, type[s] of insulin) and < or =15% change in the average total daily dose of insulin (ie, average over 1 week to account for day to day variability, changes < or =15% over the preceding 12 weeks). • FPG <270 mg/dL (15 mmol/L) at Week -2. Note: at the investigator’s discretion, based upon review of recent SMBG values, subjects not meeting the Week -2 FPG criteria may return to the investigational site within 7 days for a 1-time repeat FPG and continue in the study if the subject’s repeat FPG meets the criterion. • Site fasting fingerstick glucose of > or =110 mg/dL (6.1 mmol/L) and <270 mg/dL (15 mmol/L) on Day 1. Note: at the investigator’s discretion, based upon review of recent SMBG values, subjects not meeting the Day 1 criteria may return to the investigational site within 7 days for a 1-time repeat fingerstick glucose and continue in the study if the subject’s repeat fingerstick glucose meets the criterion. • Adequate compliance with the run-in period study procedures, including performance of the SMBG measurements (completed at least 3 or more SMBG measurements per week) with appropriate diary entries, and ≥80% compliance (by pill count) with single-blind placebo capsules • Body mass index > or =20 to < or =40 kg/m2 • Willing and able to adhere to the prohibitions and restrictions specified in this protocol • Subjects must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study. • To participate in the optional pharmacogenomic component of this study, subjects must have signed the informed consent form for pharmacogenomic research indicating willingness to participate in the pharmacogenomic component of the study (where local regulations permit). Refusal to give consent for this component does not exclude a subject from participation in the clinical study.
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E.4 | Principal exclusion criteria |
Diabetes-related or Metabolic • History of diabetic ketoacidosis, T1DM, pancreas or beta-cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy • Repeated FPG and/or fasting SMBG measurements > or =270 mg/dL (15 mmol/L) during the pretreatment phase, despite reinforcement of diet and exercise counseling • Have proliferative diabetic retinopathy for which treatment is planned during the course of the study • History of 1 or more severe hypoglycemic episode within 6 months before screening • History of hereditary glucose-galactose malabsorption or primary renal glucosuria • Ongoing, inadequately controlled thyroid disorder • Ongoing eating disorder or significant weight loss or weight gain within 12 weeks before the screening visit, defined as an increase or decrease of 5% in body weight based upon clinic-based measurement or, if not available, subject report Muscular/Skeletal • Use of a bisphosphonate within 12 months prior to screening or expected to receive treatment with bisphosphonate during the study period • If on medication treatment for osteoporosis (eg, estrogen replacement, selective estrogen receptor modulator [SERM] therapy, or calcitonin), not on a stable regimen (for at least 6 months prior to screening) • T score < -2.5 (at any site) in a subject not currently on treatment • Treatment with a corticosteroid medication within 3 months prior to screening (for more than a total of 14 days in duration) or likely to require treatment with a corticosteroid medication during the subject's participation in the study • Parathyroid hormone (teriparatide) treatment within 12 months prior to screening • Severe vitamin D deficiency with serum 25-hydroxy vitamin D level < or =10 ng/mL at screening or within 12 months prior to screening • Hypercalcemia • History of rheumatoid or other inflammatory arthritis • Conditions that interfere with accurate measurement of BMD • Non-healed fracture, or any fracture with 12 months of screening • Acquired or inherited bone disorders that may confound assessment of bone density or bone turnover or elevation of alkaline phosphatase >1.5xULN Renal/Cardiovascular • Renal disease that required treatment with immunosuppressive therapy or a history of dialysis or renal transplant. • Myocardial infarction, unstable angina, revascularization procedure, or cerebrovascular accident within 3 months before screening, or revascularization procedure is planned, or subject has a history of New York Heart Association (NYHA) Class III-IV cardiac disease (refer to Attachment 3, New York Heart Association Classification of Cardiac Disease, for a description of the classes). • Findings on 12-lead ECG that would require urgent diagnostic evaluation or intervention • Uncontrolled hypertension (ie, using an average of 3 seated blood pressure readings with a diastolic blood pressure > or =100 mmHg or systolic blood pressure > or =160 mmHg) at Week -2. Gastrointestinal • History of hepatitis B surface antigen or hepatitis C antibody positive (unless associated with documented persistently stable/normal range aspartate aminotransferase [AST] and ALT levels), or other clinically active liver disease. • History of prior bariatric surgical procedure within 3 years before the screening visit. Laboratory • Estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2 • For subjects taking metformin: serum creatinine > or =1.4 mg/dL (124 micromol/L) for men and > or =1.3 mg/dL (115 micromol/L) for women; no contraindication to the use of metformin (including eGFR) based upon the label of the country of the investigational site • Fasting serum triglycerides > or =600 mg/dL (6.74 mmol/L) at screening (or subsequent visit if not fasting at screening). • Alanine aminotransferase level >2.0 times the ULN or total bilirubin >1.5 times the ULN at screening Other conditions • History of malignancy within 5 years before screening • Clinically important hematologic disorder • History of positive human immunodeficiency virus (HIV) antibody • Investigator’s assessment that the subject’s life expectancy is less than 2 years • Any condition that in the opinion of the investigator would make participation not in the best interest of the subject, or could prevent, limit, or confound the protocol specified assessments Medications/Therapies • Current use of any other SGLT-2 inhibitor • Subjects receiving anti-hypertensive or anti-hyperlipidemic therapy not on a stable regimen (same medication and dose[s]) for at least 4 weeks before Day 1 • Known allergies, hypersensitivity, or intolerance to canagliflozin or its excipients (refer to Section 14.1, Physical Description of Study Drugs)
For a complete list, please refer to section 4.3 of the protocol.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be the change in HbA1c from baseline to Week 26. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Pretreatment phase (screening and single-blind placebo run-in); then a double blind treatment phase |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial is the last visit of the last subject undergoing the trial. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 8 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 5 |